Mutations in the lamin A/C gene on chromosome 1 and the emerin gene on the X chromosome both can cause Emery-Dreifuss muscular dystrophy (EDMD), but the precise mechanisms by which they do so are still being identified.

Now, a multinational team has found that, in mice with an EDMD-like disease, lamin protein defects interfere with the way cell nuclei normally localize in skeletal-muscle fibers at the point where each fiber receives signals from a nerve cell.

The researchers say their results “strongly indicate” that defects at the neuromuscular junction (where nerve and muscle connect) contribute to the lamin A/C type of human EDMD, and provide insights into at least one cellular and molecular mechanism operating in this disease.

The team, coordinated by Tom Misteli at the National Cancer Institute of the National Institutes of Health in Bethesda, Md., published its findings Jan. 5, 2009, in the Journal of Cell Biology. Investigators found that the neuromuscular junctions are abnormally organized in these mice and that nerve-to-muscle signals are altered. They say humans with lamin A/C-related EDMD show similar molecular defects in their muscles.

MDA grantee Howard Worman at Columbia University, who has conducted several studies of the molecular consequences of EDMD, cautions that heart-muscle cells, which are severely affected in lamin-related EDMD, do not have neuromuscular junctions, demonstrating that a different disease mechanism exists in these cells.

In October 2008, Worman’s group identified a signaling pathway in the heart called ERK as a mechanism of cardiac damage in lamin A/C-related EDMD. (See Research Updates, Winter 2009.)

The identification of small molecules that can block the genetic defect that causes type 1 myotonic dystrophy (MMD1, DM1) may be the first step toward developing a new drug treatment for the disease, say researchers at the University of Rochester (N.Y.) Medical Center (URMC).

The abnormality that underlies MMD1 is a stretch of genetic material derived from DNA on chromosome 19 that contains more than the usual number of a repeating chemical sequence known as a CUG (cytosine, uracil, guanine) triplet repeat.

A major effect of the CUG triplet repeats in RNA (genetic instructions derived from DNA) is the entrapment and disabling of a protein called MBNL1, also known as muscleblind 1. Normally, MBNL1 helps build cellular channels for chloride ions, which are essential for muscle function. But when it’s stuck to CUG triplet repeats, it can’t play this role.

The newly identified small molecules prevent MBNL1 from becoming ensnared in the CUG triplet repeat trap, freeing it to do its usual job helping muscle function.

The molecules potentially could be developed into a therapy that would prevent the toxic interaction between MBNL1 and CUG triplet repeats and treat the disease.

A research team led by chemist Benjamin Miller published its findings online Nov. 7, 2008, in the Journal of the American Chemical Society. The team included neurologist Charles Thornton, who co-directs the MDA-supported clinic at URMC and who has received MDA funding for MMD1 research.

“This is an important first step toward developing a drug treatment for myotonic dystrophy,” Thornton said. “The message from our patients is loud and clear — push this forward as fast as possible.”

Molecular silencing of so-called SMN2 genes, known to be beneficial in patients with spinal muscular atrophy (SMA), all of whom lack functional SMN1 genes, has recently been found to play a role in how beneficial SMN2 genes are in this disease.

The severity of SMA correlates in general with the number of SMN2 genes a person has; the more SMN2 genes, the milder the disease usually is. (See “In Focus: SMA.”)

However, researchers have noted many exceptions to the “more SMN2 genes, milder disease” principle in this disorder of motor neurons (muscle-controlling nerve cells) in the spinal cord.

Now, German and Australian researchers coordinated by Eric Hahnen at the University of Cologne (Germany) have found that some SMN2 genes are inactive because they’re tagged with a chemical grouping of a carbon and three hydrogen molecules (“methyl” group) that keeps them “silent.” Drugs known as histone deacetylase (HDAC) inhibitors, which are already being tested in SMA, can help remove these methyl groups.

In laboratory experiments, Hahnen’s team found two HDAC inhibitors, vorinostat and romidepsin, were particularly good at bypassing silencing of the SMN2 gene. They suggest these compounds be tried in SMA.

In a development that could lead to better screening of drugs for spinal muscular atrophy (SMA), skin cells from a child with type 1 SMA have been “reprogrammed” back to a stem-like state and then coaxed to develop into SMA-affected motor neurons, the nerve cells that normally control muscle movement but malfunction and die in this disease.

Allison Ebert, assistant scientist in the laboratory of Clive Svendsen at the University of Wisconsin-Madison, and colleagues, who published their findings online Dec. 21, 2008, in the journal Nature, say the results will allow the study of SMA in motor neurons in the lab and probably will allow drugs for SMA to be screened more effectively than is currently possible.

Although they note that further testing is necessary, so far they believe the child’s SMA-affected cells faithfully reproduce the SMA disease process and haven’t been altered by the reprogramming procedure — a critical feature for accurate research.

The investigators also took skin cells from the child’s unaffected mother and treated them the same way as the child’s cells. In contrast to the child’s cells, the mother’s unaffected motor neurons are developing normally, they say.

The research team included Christian Lorson, associate professor at the University of Missouri-Columbia, who has MDA funding for SMA work. Lorson, with graduate students Virginia Mattis and Frankie Rose, analyzed cellular levels of the SMN protein, a deficiency of which is the root cause of SMA.

The SMA-affected motor neurons in the current study have also responded positively to compounds known to increase SMN protein levels. Raising SMN levels to save motor neurons is a major goal of current SMA drug development.

The researchers note that “this new model should provide a unique platform for studies aimed at both understanding SMA disease mechanisms that lead to motor neuron dysfunction and death, and the potential discovery of new compounds to treat this devastating disorder.”

A defense mechanism called “autophagy” that neurons (nerve cells) use to protect themselves from dangerous misfolded proteins may hold promise for developing treatments for spinal-bulbar muscular atrophy (SBMA, Kennedy disease) and perhaps similar neurodegenerative diseases, new research shows.

Autophagy, which means “self-digestion,” is used by cells to degrade protein molecules that have folded into dangerous shapes that can cause cell death. (SBMA-affected cells attempt to utilize this mechanism, but it’s insufficient in these cells.) Many neurological and neuromuscular diseases involve overproduction of and damage from misfolded protein molecules, because neurons are exquisitely vulnerable to misfolded protein stress.

Until now, studying autophagy with the aim of exploiting its possible therapeutic effects has been technically difficult, and attempts to induce it in the laboratory have destroyed cells.

But MDA grantee Albert La Spada and co-workers at the University of Washington Medical Center in Seattle recently found a new and convenient way to study autophagy. They published their findings online Nov. 18, 2008, in the Journal of Biological Chemistry.

La Spada and colleagues found that depriving neurons of certain nutrients while they’re being maintained in the lab can induce autophagy without killing the cells, giving the researchers a valuable window on the process.

They found that, in the laboratory, neurons producing misfolded androgen receptor protein molecules, which cause cell death in SBMA, were protected by enhanced autophagy after they were deprived of selected nutrients.

Knowing more about this neuroprotective pathway and how it might be enhanced in disease-affected neurons “will better guide strategies for therapy development,” the researchers say.

In January, MDA began funding development of the North American CMT Network to provide an infrastructure for clinical research in Charcot-Marie-Tooth disease (CMT) to aid researchers in locating potential participants for clinical studies. An early goal is to establish scoring systems for functional evaluations in children with CMT.

Neurologist and neuroscientist George Karpati, a longtime MDA grantee at the Montreal Neurological Institute, passed away suddenly on Feb. 6, 2009. The Institute is part of McGill University.

Karpati held the I.W. Killam Chair and was a professor of neurology and neurosurgery at McGill. He made significant contributions to the field of neuromuscular disorders in general, focusing specifically on gene therapy and the augmentation of the utrophin protein as potential treatments for Duchenne muscular dystrophy (DMD) since the 1990s.

In addition to his substantial research contributions, he was known for his clinical acumen and compassion for patients and families.